Open AccessStructural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1
Author(s) -
Xiaoling Ni,
David Heidenreich,
Thomas Christott,
James M. Bennett,
Moses Moustakim,
Paul E. Brennan,
Oleg Fedorov,
Stefan Knapp,
A. Chaikuad
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00460
Subject(s) - piperazine , moiety , benzimidazole , combinatorial chemistry , chemistry , urea , lysine , amide , domain (mathematical analysis) , benzoxazole , computational biology , stereochemistry , biochemistry , amino acid , biology , organic chemistry , mathematical analysis , mathematics
YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.